We will continue to center on one manifestation of the nonadaptive immune system, H-2-associated natural resistance (H-2NR). H-2NR can be defined as the nonadaptive rejection and decreased survival in the spleens and lungs of allogeneic or semisyngeneic normal or malignant hemopoietically derived cells as a consequence of nonidentity with the host at the major histocompatibility complex (MHC). The best known example of H-2NR is genetic resistance to H-2 nonidentical CFU-S proliferation in certain combinations of donors and irradiated hosts. By monitoring the death and metastatic distribution of 131I-iododeoxyuridine prelabeled leukemia cells we demonstrated that all mouse strains tested were able to recognize and resist cells which were not identical with self at either the K or D regions of H-2. Non-H-2 genes control the radiosusceptibility of H-2NR, and resistance by mice of the C57BL family is H-2D (Hh-1) restricted only after irradiation. The natural killer (NK) family of effector cells is clearly involved in H-2NR. Analysis of the genetic control of H-2NR will procede through utilization of test crosses and recombinant inbred strains, and will aid in determining its relationship with NK cells. Experiments are proposed to determine whether NK cells recognize H-2-associated target structures on the transplanted cells or whether NK-mediated lysis is H-2 independent with the H-2 effect involving either stimulation of NK activity or H-2 restriction of the positioning of the injected cells. A major portion of this project is aimed at determining the role of H-2 translation products in H-2NR. We will compare the susceptibility to H-2NR and the H-2 antigen expression of leukemia cells cloned from syngeneic, semisyngeneic, and allogeneic mice. Flow cytofluorimetric techniques will allow us to discriminate between stable genotypic and transient phenotypic alterations in H-2 expression. In addition, we will examine the interrelationship between nonadaptive immunity and the subsequent development of the adaptive immune response with emphasis on single gene mutants and the regulation of the F1 antiparent immune response in vitro. The final area of emphasis is examination of the possibility that H-2NR is a manifestation of a surveillance system against neoplasia and metastasis. The study of H-2NR also will provide valuable insight into the evolution of adaptive immunity, the control of hemopoiesis and cell interactions, and the physiological functions of the MHC.